PT98442B - METHOD FOR THE PREPARATION OF THE POLYMERIC SYSTEM FOR ADMINISTRATION OF A DRUG - Google Patents

Abstract

Cross-linked controlled density polyamines which are water-insoluble and swell at pH values up to about 8 are shown. These polyamines are useful in site-specific drug delivery systems.

Description

The present invention relates to oral drug delivery systems for the administration of specific drugs. In particular, the present invention relates to drug delivery systems in which a drug is covalently linked to a polymeric material to be administered to a specific site, taking into account the pH of the site where the drug is to be administered. . The present invention relates especially to an administration system for administering a medicament to a medium with a pH up to about 7, such as that which can be found in the gastric system.

2. Prior Art

Various attempts to obtain controlled oral administration of certain drugs have been reported. Most of these attempts are directed at prolonged release in vivo and use a polymeric material as a vehicle, coating or release rate limiting barrier, for example, as a membrane. A sustained release delivery system uses chemical bonds to control the release. Ferruti et al, U.S. Patent No. 4,228,152, discloses a system of administration of the polymeric prolonged release prostaglandin in which a prostaglandin is directly linked or via an oxyalkylenic, aminoalkylenic or oxyaminoalkylenic chain to a polyacrylic or polymethacrylic structure. It is described that, after entering the body, prostaglandins are hydrolyzed, causing their release into the body over extended periods of time.

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Some systems, however, have targeted certain drug administrations where the administration of a drug is limited to a specific tissue or organ. One of these systems is disclosed by Saffron, in U.S. Patent No. 4,663,308. Saffron discloses a polymeric drug delivery system for localized drug delivery, wherein the drug is coated with a polymer that is cross-linked with an azo compound. It is said that the azo bonds are reduced by the reductases in the large intestine, causing the degradation of the polymeric coating, which causes, therefore, the release of the drug in that area of the intestine. Others of these systems are disclosed by Siegel et al, in J. Controlled Release, 8, 179-182 (1988). Siegel et al disclose hydrophobic polyamine hydrogels useful for the administration of a regional screening at non-neutral pH values.

SUMMARY OF THE INVENTION the present invention relates to the localized administration of drugs by oral administration of an acid pH dependent drug delivery system. One aspect of the drug delivery system in question involves the release of a drug into an acidic medium, such as a gastric medium that normally has a pH value between about 1 and about 4. In this system, the medicine can be covalently linked to the polymeric structure or to a functional group pendent from the polymeric structure and can be released from the polymer by hydrolytic cleavage of the covalent bond at a pH below about 7. The drug can be incorporated into the polymer via a pH sensitive linker, to which the drug can be covalently linked and whose covalent bond is cleaved at pH values below about 7, and never at higher values, thus, releasing the medicine at high pH values, such as about 7 or higher, is inhibited. In another aspect, the present drug delivery system involves methods of covalently attaching drugs to polymeric materials by means of chemical linkers and in particular involves methods for incorporating drugs into polymers via pH sensitive linkers.

According to another aspect of the present invention, the polymeric material can be adapted to swell at pH values of about 1-7 to increase the effective amount of drug released. The medicament can be covalently attached to the polymer, as described above, via a pH-sensitive linker, such that when the polymer swells after exposure to the acidic environment, the release of the medicament into the gastric environment is facilitated.

In particular, the invention relates to a delivery system adapted for releasing an active ingredient at pH values up to about 7 and for inhibiting the release of the active ingredient at pH values above 7. The delivery system comprises a polymeric material covalently linked to the active ingredient through a silyl bond that is sensitive to pH and is capable of being cleaved at pH values up to about 7.

BRIEF DESCRIPTION OF THE DRAWINGS The present invention should be understood taking into account the following Detailed Description and the attached drawing comprising Figure 1. This figure is a graph illustrating the pharmacokinetic properties (plasma concentration) of an administration system in which the drug misoprostol is administered to male rats, compared to a pharmaceutical composition containing non-covalently bound misoprostol. The graph is a curve of the concentration of misoprostol free acid in picograms per milliliter versus time in hours,

DETAILED DESCRIPTION OF THE INVENTION the present invention relates to drug delivery systems to certain locations for delivering a drug to the gastric system, namely to the stomach, where the drug is covalently linked to a polymeric material adapted to release * an effective amount of drug at pH values below 7, without any significant amount of the drug being released at higher pH values.

In particular, the invention relates to an administration system for releasing an active ingredient in the stomach at pH values from 1 to about 4 and for inhibiting the release of the active ingredient at pH values greater than about 7.0 The delivery system comprises a polymeric material covalently linked to the active ingredient via a covalent bond that is sensitive to pH and is capable of being cleaved at pH values up to about 4,

According to a specially preferred embodiment of the invention, the polymeric materials are adapted to swell at pH values of about 1-7, with the release of an effective amount of the medicament. Polymeric materials that exhibit these swelling properties are especially preferred for use in administering the active ingredient to the stomach, as the swelling of the polymer provides a greater opportunity for the active ingredient to be exposed to the acidic conditions of the stomach and thereby I know 'cleaved and released from the administration system.

In particular, the invention relates to an administration system adapted to release an active ingredient in the stomach at pH values from 1 to about 4 and to inhibit the release of the active ingredient at pH values greater than about 7, wherein said system swells within that range of pH values. The delivery system comprises a swellable polymeric material eovalently linked to the active ingredient via a covalent bond that is sensitive to pH and is capable of being cleaved at pH values up to values close to 7.

The present invention also comprises a polymeric delivery system in which the polymer can be modified by fixing auxiliary groups that can transmit or increase certain properties, such as gastric retention, hydrophilicity, crystallinity, swelling, etc., which can affect the rate of drug release. For example, auxiliary groups such as dialkylamino groups or quaternary ammonium salts can be employed to transmit or increase these properties.

The terms medicine and active ingredient are used interchangeably to describe a compound that is intended to be administered to a site in the body for delivery. The delivery system may comprise the incorporation of more than one active ingredient, in situations where it may be therapeutically beneficial to administer or co-administer more than one active ingredient. Suitable medicaments or active ingredients useful for the present invention are those usually classified as medicinal agents and which are able to be incorporated into the polymeric material and to form a pH sensitive (pH 1-7) covalent bond with the polymeric material. For example, suitable active ingredients that can be used in the practice of the present invention can be those compounds that contain a hydroxyl group (-OH), a carboxylic acid group (-COOH), an amino group (-NHg or a -NHR group) where R is an alkyl group with 1-4 carbon atoms), a thiol group (-SH), or an enollable carbonyl group (ie, aldehydes, ketones and amides).

Exemplary active ingredients are those medicinal agents in which gastric release is preferred over intestinal release. or in which control of the rate of release of the active agent is desired to achieve systemic action. For example, medications, in which administration to the stomach is preferred, may be natural or synthetic prostaglandins and prostacyclins (for example misoprostol, enisoprost, enprostil, iloprost, and arbaprostil). any medication for treating peptic ulcers, gastric antisecretory medications, antimicrobial medications, prokinetic medications, cytoprotective medications, etc. Exemplary antimicrobial drugs are tetracycline, metronidazole and erythromycin, which can be used to eliminate gastric myocrobes, such as Heliobacter pylori which can cause or contribute to gastric ulceration. Antimicrobial agents comprise a class of active ingredients. for which it may be therapeutically beneficial to administer it together with more than one antimicrobial agent, using the prescribed administration system, due to differences in the spectrum of antimicrobial efficacy of each agent. The active ingredients also comprise agents that act systemically, which do not act directly on the stomach, but which can be readily administered to the stomach for controlled release, absorption and systemic action. Examples of these drugs are those that have a relatively short duration of action and for which prolonged and continuous plasma levels of the active ingredient are desired, delivery system is especially useful for administration of active ingredients that are prostaglandin analogous to the structure

or

wherein R represents hydrogen or lower alkyl with 1 to 6 carbon atoms; R represents hydrogen, vinyl or lower alkyl having 1 to 4 carbon atoms and the wavy line represents stereochemistry R or S; R ^, and R. are hydrogen or lower ώ <S 4 alkyl with 1 to 4 carbon atoms or Rg and Rg together with carbon Y form a cycloalkenyl with 4 to 6 carbon atoms, or Rg and R ^ together with the X and Y carbons they form a cycloalkenyl with 4 to 6 carbon atoms, where the XY bond can be saturated or unsaturated.

Especially preferred prostaglandins can be the prostaglandin analogue misoprostol, (±) 1 les, 16-dihydroxy-16-methyl-9-oxoprost-13E-en-1-oate with the following structural formula

Another prostaglandin analogue that can be administered by the present system is enisoprost, (+) 11a, 16-dihydroxy-16-methyl-9-oxoprost-4Z, 13E-diene-1-methyl oate, which has the following formula structural

OR

OH

Another prostaglandin analogue that can be administered by the present system is the prostaglandin analogue which has the following structural formula

active ingredient is present in the compositions of this invention in an amount sufficient to prevent, cure and / or treat a disease for a desired period of time and for which the composition of this invention must be administered. This amount is referred to herein as the effective amount. As is well known, especially in medicine, the effective amounts of medicinal agents vary depending on the particular agent employed, the disease to be treated and the rate of elimination from the body of the composition containing the medicinal agent, as well as vary according to the individual. to be treated and their body weight. An effective amount is the amount that in a composition of this invention provides a sufficient amount of the active ingredient that achieves the required activity of the active ingredient in the body to be treated for the desired period of time and may be less than the amount normally used.

Since the amounts of certain active ingredients suitable for the treatment of certain diseases are normally known, it is a relatively easy laboratory task to formulate a series of compositions of this invention for release that contain a range of these active ingredients, to determine the effective amount. of such an active ingredient for a given composition of this invention. Based on reading this description and the following examples, a person skilled in the art can select an amount of a particular active ingredient and covalently attach it to one of the polymers described herein for administration of an effective amount of said active ingredient. While the effective amount for all active ingredients cannot be defined, the typical compositions of this invention can contain from about one microgram to about one gram of active ingredient per administered dose. Most preferably, a composition of this invention can contain from about one microgram to about 250 milligrams per dose.

Medicines or medicinal agents can be covalently bonded to a polymeric material, in accordance with the teachings of the present invention, for release in an acidic environment. depending on the desired physiological action of the medication. the systemic side effects associated with each medication, the speed of decomposition of the medication in a given environment and other factors well known in medicine.

For administration of a medicament to an acidic environment, suitable polymeric materials are those that are capable of forming a covalent bond with the active ingredient or that are capable of being adapted to form a covalent bond with the active ingredient, where the bond covalent is sensitive to pH and is capable of being cleaved at pH values up to about 7. Polymeric materials, which cannot form this covalent bond themselves, can be modified by fixing a linker group to said polymer. The linker group can be any suitable compound that can bind to the polymer and the active ingredient. A covalent bond can be formed between the active ingredient and such a fixed linker group, or else the active ingredient can be covalently attached to a linker group and the linker / active ingredient group can be attached to the polymer.

The covalent bonds that can be cleaved under acidic conditions can be bonds of the following types: silyl ethers and esters, acetals, thioacetals, imines, amines, carbonates and vinyl ethers. A preferred covalent bond that can be cleaved within the preferred pH range is the silyl ether covalent bond. Covalent silyl ether bonds are especially preferred because this bond can be formed between a silyl functional group on the polymer (or linker group) and any hydroxyl functional groups on the active ingredient.

It is preferable that the polymeric materials chosen for the practice of the invention are non-absorbable and practically non-absorbable in the patient's body. These polymeric materials are not absorbed or metabolized by the body and therefore are beneficial for use as a vehicle for the drug, since these polymers are practically physiologically inactive. For example, high molecular weight polymers, for example 1,000-160,000 Ρ, charged or polymers of m

cross-links or polymers that are insoluble under physiologically acidic conditions (such as cross-linking), eliminate or significantly reduce polymer transport through the small intestine wall. Exemplary polymeric materials are polyamines, polybutadienes, copolymers of 1,3-dienes, polysaccharides, hydroxypropylmethylcellulose and polymers of acrylic or methacrylic acid, including their copolymers, maleic copolymers, and any polymer with derivable olefinic bonds, the term copolymer is used herein. the meaning of mixed polymers (such as polybutadiene) that contain more than one polymer. A preferred polymer is a polymer selected from polyamine, polybutadiene, 1,3-diene copolymers and any polymer with a derivable olefinic bond. An especially preferred polymer is a polymer that is a functionalized polybutadiene that contains amino functional groups. Such a polymer is preferred because the functional amino groups are able to bind with an active ingredient or with a linker group. For example, for an amino-functionalized polybutadiene, a chlorodimethylsilane linker and an active ingredient containing a hydroxyl group form a silyl ether bond in which the cleavage can take place in a pH range of about 1 to 5.

Another group of preferred polymeric materials are polymers that are prepared to swell at pH values of about 1 to 7. Polymers that can swell in the desired pH range for cleavage of the covalent bond, increase the cleavage of these bonds and thereby the release of an effective amount of medicine. The exemplary polymeric materials that manifest these swelling characteristics are polyamines and their quaternary salts.

In order to make some of these polymers insoluble under acidic conditions, the polymers can be crosslinked by methods known in the art. For example, crosslinking agents can be employed, or crosslinking of the polymer free radical can be performed. The crossing of bonds is carried out to an extent sufficient to render the polymer insoluble without significantly affecting its release characteristics. Crosslinking is not necessary to render the polymer insoluble, as the solubility of the polymer can also be affected by its molecular weight.

The crosslinking agent selected to be incorporated into the delivery system can be any suitable crosslinking agent that can crosslink the polymer selected for use in the system. The selection of a crosslinking agent is within the capabilities of the person skilled in the polymer art. Depending on the selected polymer. the crosslinking agent can be an aldehyde, a diacid, a disilane, a dialosylene, a tri (halomethyl) benzene, a dialoalkane, a dialoalkene, a diallyl halide, or any polyaromatic, aliphatic or allyl halide, etc.

Some of the polymers that can be used here can also be modified by fixing auxiliary groups that can transmit certain properties, such as gastric retention, hydrophilicity. Christianity, etc. For example, auxiliary groups, such as dialkylamino groups or quaternized ammonium salts, can be employed to control certain properties, such as hydrophilicity, swelling, christianity, etc., in order to affect the release rate of medicine.

medicament is incorporated into the polymer by means of covalent attachment of the medicament to the polymeric material, for example to the main structure of the polymer or to certain pending functional groups, by means of a covalent bond that can be cleaved to release an effective amount of the medicament under acidic conditions physiological. The medicament can be covalently linked to the polymeric material by means of a chemical linker, wherein the covalent link between the medicament and the linker is hydrolytically cleaved under physiological acidic conditions, to release an effective amount of the medicament.

A pH sensitive linker, as defined herein, can be incorporated into the polymeric material to effect specific local delivery to an acidic environment. If a polymeric material is not able to provide a pH sensitive covalent bond with the drug, a drug delivery system can be made for specific local administration of a drug to a gastric environment, using a pH sensitive connector, whereby the drug is hydrolytically cleaved under acidic conditions, but not under basic conditions. That is, at pH values greater than 7, there is little or no cleavage of the covalent bond to the active ingredient. The release of the active ingredient at pH values greater than 7 is thereby inhibited. The active ingredient is not released and remains covalently bound to the polymer at this high pH value.

Binders suitable for incorporating an active ingredient into a polymeric material can be pH sensitive binders that are cleaved at pH values from 1 to about 7, but not at values greater than 7. For specific local administration to an acidic environment, these linkers are sensitive to pH and preferably can be hydrolyzed to pH values less than about 7. Exemplary linkers can be acetal, thioacetal, imine, aminal, carbonate, vinyl ether and silyl ether or ester type linkers. Preferred linkers for use in the present system can be pH sensitive linkages selected from the group consisting of linkers formed using chlorodiisopropylIsilane, chlorisopropylethylsilane. chlorodimethylsilane. chlorodiphenylsilane, 1- (di-methylchlorosyl) -2- (m, p-chloromethylphenyl) -ethane and 1,1,4,4-tetramethyl1-1.4-dichlorosilyl-ethylene. The most preferred binders for use in the present system are selected from chlorodiisopropylsilane and eloroisopropylethylsilane. '·> ¹

Suitable linkers for incorporating a drug into a polymeric material, where the drug is first linked to the linker and the linker / drug is linked to the polymer can be any suitable linkers that have the above functional groups and a functional group capable of bind to the polymer. Two or more different linkers can be used in order to affect the overall rate of drug release from the present polymeric system.

A preferred linker for administering a medicament to an acidic environment is one that forms a covalent bond through a silyl linker represented by the formula:

I

P-Si-Y-D

I

R ₂ where P represents the polymeric material, Y can be 0, or a -COO group of an -OH or -COOH group that is present in the active drug, and D represents a drug with a hydroxyl, a carboxylic acid, or a enolizable carbonyl group, to form the bond Si-Y and R. and R „independently represent H, or substituted or unsubstituted alkyl radicals, cycloalkyl, alkenyl, alkynyl, aryl, alkaryl or aralkyl .

An especially preferred linker for administering a medicament to an acidic environment will be one that forms a covalent bond through a silyl ether linker represented by the formula:

I

I ^χ

P-Si-O-D

I

R ₂ where P represents the polymeric material, 0 is oxygen from a hydroxyl group that is present in the active drug, and D represents a drug with a hydroxyl group, where H is removed to form a sodium ether linker 0 and R ^ and R £ independently represent H, or the substituted or unsubstituted alkyl, cycloalkyl, alkenyl, alkynyl, aryl, alkaryl or aralkyl radicals. This preferred acid-sensitive binder is readily hydrolyzable at pH values of 1 to about 7. However, at pH values of about 7 or higher it is not significantly hydrolyzed. Exemplary silyl ether bonds include those formed using chlorodiisopropylsilane, chloroisopropylethylsilane, chlorodimethylsilane, chlorodiphenylsilane, l- (dimethylchlorosylyl) -2- (m, p-chloromethylphenyl) ethane and 1,1,4, 4-tetramethi1-1,4-dichlorodisilylethylene, chlorophenylmethylsilane, chlorodiethylsilane, chlorine (t-butyl) methylsilane, and chloroisobutylpropylsilane.

These pH sensitive ligators can also be used to incorporate a drug into a polymer that is prepared to swell at pH values of about 1 to 7, in order to complement the drug administration. In this way, the acid-sensitive linker can be employed to covalently bond a drug to a polymeric material that is adapted to swell at pH values of about 1 to 7, with the release of an effective amount of the drug.

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1-3

A wide variety of methods can be employed to covalently link the drug to the polymer via the linker. For example, the linker may be a functional group pendant from the polymer to which the drug is attached; or the linker can be reacted with the drug and the linker / drug can then be linked to the polymer, or the linker can be reacted with the polymer and then with the drug.

Representation of the present polymeric drug delivery system can be synthesized in the manner described above and as shown in the general reaction / preparatory schemes here. General Scheme 1 illustrates a scheme for a delivery system where a functional polymer is formed. The drug is attached to the functionalized polymer through a linker group. The linker group can be attached to the functionalized polymer before covalent attachment to the drug occurs (alternative step 1), or else the linker group can be covalently attached first to the drug and the linker / drug can then be attached to the functionalized polymer (alternative step 2). The polymer / drug system can be crosslinked, but it is not necessary if the selected polymer has sufficient molecular weight to provide insolubility and non-absorbability.

GENERAL SCHEME 1

Base Polymer ------------> Functional Polymer (1) linker + medicine or (2) linker - medicine [Functional Polymer] - [linker] -Medical cross-linking

Cross-links {[Functional Polymer] - [linker] -Medication}

GENERAL SCHEME 2

Base Polymer ------------> Cross-linked Functional Polymer [Functional Polymer Cross-links Connector 1-drug connector [Functional Polymer] Cross-links - Drug link [Functional Polymer Cross-links - Link - Drug

General Scheme 2 shows a reaction sequence for the formation of a functionalized polymer from a base polymer, followed by crossing bonds of the functionalized polymer. The active drug component can be fixed first by fixing a linker group, followed by the drug. or else the drug can be eovalently attached to the linker group before attaching the drug linker to the functionalized polymer and with the links already crossed.

In the following Scheme 3, a general sequence of steps is illustrated and in Scheme 4 a more specific sequence of steps for the formation of the present administration system is illustrated. The present drug delivery system can be prepared according to the schemes shown in these two reaction schemes. Scheme 3 shows that a polymer can be hydroformylated and reductively aminated to place a predetermined percentage of alkylamino functional groups on the polymer backbone. The extent (percentage) of amino functional groups can be selected and changed to the

vary the rate of release of the active ingredient. functionalized polymer is hydrosilylated and reacted with drug to be eovalently bound to the polymer, polymer is subjected to crosslinking, which can be followed by quaternization of any remaining amount of alkylamino groups. R, R 'and R' 'in Scheme 3 can be alkyl, aralkyl. aryl or alkenyl.

Scheme 4 illustrates a more specific example,

A polybutadiene with a molecular weight (P of about 1,000 to

160,000 is functionalized by hydroformylation which is followed by reductive amination to place a predetermined percentage of functional dimethylamino groups on the polymer backbone. The resulting functionalized polymer is hydrosilylated and reacted at room temperature with the drug prostaglandin, misoprostol. This step eovalently binds misoprostol through a covalent bond of silicon-oxygen to the hydroxyl group C-11 of the misoprostol, the polymer is subjected to crossing of connections with tx ,, «'-dichloro-p-xylene. 0 polymer with i t

cross-linking can be quaternized by quaternizing the remaining dimethylamino groups with methyl chloride.

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Medication

SCHEME

^z ( ^e HO) hT | ΟΗθ 'OHO

N ^Z ( ^C HO)

JZ cr

i o

<75x

the ω

O

B.

Q.

O

Ul

CM

The H

O

O .

ca x * °

N (CH ₃ ) to N (CH ₃ ) ₂ ^N ^ ^CH ^ ^{2 n} ( ^CH 3) 2

Without further elaboration, it is believed that one skilled in the art can, using the foregoing description, use the present invention to its fullest extent. The following specific preferred embodiments are illustrative of the present invention.

The following examples 1 to 24 illustrate drug delivery systems in accordance with the teachings of the present invention, wherein the active ingredient is covalently bound to a polymeric material with the release of an effective amount of the active ingredient at pH values of about 1 to 7. The active ingredient is incorporated into the polymer by means of a pH sensitive chemical linker.

Example 1

This example refers to a medication delivery system where misoprostol is incorporated into a polyamide via a silyl ether linker. A linker group is attached to the polymer and the active ingredient, misoprostol, is covalently attached to the polymer-linker system,

A 75 g sample of Polybutadiene (Aldrich 20.050-6

45% vinyl P = 4,500) was dissolved in 75 ml of toluene. Under a N _o atmosphere, this polymeric solution was poured into an autoclave ion of 300 ml. Then, 3.3 g of triphenylphosphine and 0.07 g of hydridorhodiocarbonyltristriphenylphosphine were added to the autoclave under Ng. The autoclave was

Ng by pressurizing the autoclave and then the Ng gas was extracted by heating it to 80 ° C - under a pressure of 2

After removing N, the autoclave (300 psi) with 1: 1 CO / Hg at 80 ° C, closed and degassed with

14.06 kg / cm ^ (200 psi) of ventilation Ng. The autoclave was

28.12 kg / cm ¹ · (400 psi) of N „.

^ 2 was charged at 21.09 kg / cm The reaction was stirred at 1200 rpm until 0.917 moles of 1: 1 CO / H ^ were reacted. After ventilation of the autoclave, the polymeric product was removed. The autoclave was washed with 100 ml of toluene and the washes were added to the polymeric product. The product solution was concentrated to a volume of 150 ml by means of a rotary evaporator. This polymer solution was dipped slowly in a solution containing 400 ml of methanol and 100 ml of water. The solution was allowed to separate into two phases and the upper phase was removed by decantation. The polymeric phase of the bottom was dissolved in 150 ml of toluene and the previous precipitation procedure was repeated. From this process, 63.64 g 1 of polymeric product were isolated. NMR indicated that 32% of the double bonds of the polybutadiene polymer [P (bd)] were hydroformylated,

A solution of the formyl-functionalized polymer (63.14 g) in 100 ml of dry and sieved toluene and with 20 ml of methanol was placed in a 3-neck round-bottom flask equipped with a thermometer, with an addition funnel and a magnetic stirring rod. The solution was further diluted with 500 ml of tetrahydrofuran and 40 ml of methanol. After cooling to 5 ° C under nitrogen, 50 g of dimethylamine was added with stirring. After 15 minutes and through the addition funnel, 85.8 ml of a 4.5 M HCl / dioxane solution were slowly added to the solution. Finally, 17 g of sodium cyanoborohydride (sodium triacethoxy borohydride, which does not require the addition of HCl / dioxane, can also be used) via a funnel and the resulting solution was washed inside the bottle with 20 ml tetrahydrofuran. The solution was stirred for 40 hours and was allowed to warm slowly to room temperature. The polymeric solution was filtered after being stirred with 60 ml of water for one hour. The filtrate was concentrated to a volume of 200 ml and, after settling for two hours, the upper polymer phase was slowly immersed in a solution that

contained 400 ml of methanol and 100 ml of water. The lower polymeric phase * was isolated by decantation. This precipitation process was repeated. From this, 64.6 g of polyamine was isolated. Elemental analysis:% G, 80.62; % H, 11.66; % N, 6.62.

A sample of 84.5 g of a 29.6 wt% solution of the previous polyamine (25 g of polyamine) in toluene was added to a Fischer-Porter bottle that was equipped with a stirring rod. The solution was concentrated to 50 g by means of a vacuum and the emptied container was taken into the dry box. Dry toluene was added to prepare a 50% by weight solution. Next, 0.125 g of tristriphenylphosphine rhodium chloride and 12.5 g of chlorodimethylsilane were added to this solution. After capping and removing the reactor from the dry box, the solution was heated to 100 ° C for 17 hours. The solution was transferred to a dry 250 ml round bottom flask in a dry box. The solution was concentrated to

37.6 g (to remove unreacted silane) and was diluted with 1,

H NMR indicated an incorporation

100 ml of dry tetrahydrofuran, 2.0% chlorosilane.

The previous chlorosylated polyamine in THF was diluted in 100 ml of DMF (dried over alumina). After 1 hour, 0.090 g of imidazole (1.3 mmoles) and 5 ml of THF were added slowly and dropwise (other amines such as triethylamine may also be present). After 15 minutes, 0.5 g of misoprostol (1.3 mmoles) in 5 ml of THF was added and washed in the solution with 2 ml of THF. After stirring for 6 hours, 0.583 g of imidazole (8.56 mmoles) in 15 ml of THF. Then 0.411 g of methanol in 2 ml of THF was added and stirred for 16 hours. After adding another ml of methanol, the product solution was evaporated to remove all THF. The remaining DMF / polymer solution was left to stand for 1 hour in order to phase out the polymer from the DMF solvent. The upper polymer layer was separated and dried again in vacuo, to remove any traces of DMF. From this process, 20.6 g of polymeric product were isolated.

previous polymer in THF (27.5% by weight solution was stirred in a 250 round-bottom flask, 1.477 g (8.55 mmol) ml was added dropwise. Then, a, ck '-dichloro-p -xylene in 10 g of THF to the stirred polymer solution The product was set up after 4 hours and left to stand at temperature The solid product was removed with three equal parts.

environment for 20 hours, spatula and was divided into washed by the following portable process:

by use

Each portion was from a shaker

The) was stirred with 200 ml of THF for 0.5 hours and was filtered and the collected solid was washed the same way. B) THF was removed from the filtered polymer using vacuum. in ç) The polymer was washed twice with non-pure water, in

according to process a).

d) repeated a) twice.

e) the collected portions were combined and dried for 4 hours under vacuum.

From this process, 17.5 g of crosslinked polyamine were isolated. Elemental analysis:% C, 77.3; % H, 11.4; % N, 5.65; % Cl, 3.51.

The product was evaluated for swelling. The product swelled to pH values between about 1 and 7. The reaction of a 25 mg sample of this material with 3 ml of methanol and with ml of ρΗ 1 acid resulted in the release of misoprostol by HPLC.

Example 2

This example relates to a drug delivery system in which misoprostol, incorporated into the crosslinked polyamine system of Example 1, is further modified by quaternization.

An 8 g sample of the crosslinked polyamine of Example 1 and 160 ml of dry THF were stirred in a 454 g (16 oz) Fischer-Porter bottle for 4 hours. Then, 9 ml of dry methylene chloride at -78 ° C was added. After stirring for 64 hours and after removing the methylene chloride by degassing, the polymeric product was filtered. After drying under vacuum, 9.7 g of the methylated product were isolated. % C, 68.11: 7, H, 10.60; % N, 4.99; % Cl, 11.01. A 9.53 g sample of the crosslinked polymer was ground at the temperature of liquid nitrogen for 5 minutes to obtain 9.33 g of a fine powder. The ground material was placed in a mortar, 9.33 g of hydroxypropylmethylcellulose was added and mixed well with a pestle. This material was transferred to the mill at room temperature and was ground for 3 minutes. This formulation was ground in a ball mill for 9 hours and sieved through a 250 micron sieve. From this process, 17.4 g of the polymeric product (<250 microns) were collected.

methylated product (quaternized) was evaluated for swelling. The methylated product was shown to swell within the pH range of about 1 to 8. The reaction of a 50 mg sample of this material with 3 ml of methanol and with 3 ml of ρΗ 1 acid resulted in the release of misoprostol, as determined by CLAR .

The reaction of a 50 mg sample of this material with 3 ml of methanol and with 3 ml of water at pH 7 resulted in an undetectable release of misoprostol after 1 hour, as determined by HPLC.

Example 3

This example illustrates a drug delivery system in which misoprostol is incorporated into a polyamine using a silyl ether linker, where misoprostol is first attached to a linker via a silyl ether link and then the misoprostol-1 system is attached to the main polymer structure. After the misoprostol has been attached to the polyamine via the linker, the polymer is crosslinked and ground by the same process, as described in Example 2. This method of fixing misoprostol via a linker is also applicable for fixing a medicine that supports a hydroxyl to polymers such as cellulose and polysaccharides (chitosan) that do not contain carbon-carbon double bonds.

The hydroformylation reaction was carried out in a 300 ml autoclave equipped with a magnetic driven stirrer. A solution of 75 g of polybutadiene LX-16 and 108 g of toluene was placed in the autoclave, under nitrogen. Then, 3.2 g of triphenylphosphine and 0.07 g of hydridorhodiocarbonyltristriphenylphosphine were added to the autoclave. The autoclave was closed and degassed with K _o by pressurization with N _o at 14.06 kg / cm (200 psi) and then the gas was extracted by ventilation. The autoclave was heated to 80 ° C · under a pressure of 28.12 kg / cm (400 psi) of

N „. After removing the N „, the autoclave was charged with 1: 1 ^Z 9 ^ά of ΟΟ / Η ^ at 21.09 kg / cm (300 psi) and at 80 ° C. The reaction was stirred at 1200 rpm for 21.5 hours, at which time

1 react 223.5 kg / cm (3179 psi) of CO / Hg gasses. H BAÍN indicated that 56% of the polybutadiene units were hydroformylated. The product solution was filtered through a millipore filter and the filtrate was concentrated to a volume of 300 ml inside a rotary evaporator. The solution was divided into 3 parts, each of which was precipitated from methanol using the following process:

1. The solution was immersed in a stirred solution of methanol and 50 ml of water.

2. The upper layer was decanted and the lower polymeric layer was redissolved in 150 ml of toluene.

3. Steps 1 and 2 were repeated.

From this process, 93 g of the hydroformed polymer product was isolated.

A solution of formyl-functionalized polymer (20 g) in 100 ml of dry sieved toluene and 10 ml of methanol was placed in a 2-liter, 3-neck round-bottom flask, equipped with a thermometer, with an addition funnel and with a magnetic stirring rod. The solution was further diluted with 225 ml of tetrahydrofuran and 20 ml of methanol. After cooling to 5 ° C under nitrogen, 38.15 g of dimethylamine was added with stirring. After 15 minutes and through an addition funnel, 58.75 ml of a 4.5 M HCl / dioxane solution were slowly added to the solution. Finally, 12.38 g of addition funnel were added. sodium cyanoborohydride and washed in the flask with 20 ml of tetrahydrofuran. The solution was stirred for 40 hours and was allowed to warm slowly to room temperature. The polymeric solution was filtered after being stirred with 100 ml of water for one hour. The filtrate formed two layers after settling for 30 minutes. After removing the bottom water layer. the upper polymer layer was concentrated to a volume of 150 ml. Then, 500 ml of a 4/1 methanol / water solution was slowly added to the polymer / THF solution and, after 2 hours, the formation of a polymeric precipitate was obtained. This precipitation process was repeated three times. The lower polymeric phase was isolated by decanting and, after removing the solvents, 11.4 g of polyamine was isolated. % G, 77.85; % H, 11.78; % N, 8.01.

A vial containing 40.0 mg of misoprostol (0.104 mmol) was loaded and equipped with a stirring rod. After being transferred to the dry box, 620 mg of DMF and 21.4 mg (0.315 mmoles) of imidasole were added. In another flask, 26 mg (0.1046 mmoles) of 1- (dimethylchlorosylyl) -2- (m, p-chloromethylphenyl) ethane (binder) were dissolved in 370 mg of DMF. This binder / DMF solution was added to a stirred solution of misoprostol / imidazole and was stirred for 1.5 hours.

Next, 9.83 g of a 20.35 wt% solution in THF (2 g of polymer) was poured into a 100 ml round bottom flask. 4 g of DMF (dried on alumina) was added and the THF was removed by vacuum until the polymer started to separate from the solution. A few drops of THF were added to obtain a clear homogeneous solution. The final mixture was composed of 2 g of polymer, 4 g of DMF and 4.78 g of THF. Then, the misoprostol-linker system was added to this solution and stirred for 4 hours at room temperature.

In the dry box, 0.156 g of a, a'-dichloro-p-xylene (0.886 mmoles) were dissolved in 1 g of THF. After removing this solution from the dry box, this solution was added to the polymeric solution. This system was left at crossover for 60 hours.

crosslinked polymer was washed by the following process using a portable stirrer:

a) It was stirred with 200 ml of THF for 0.5 hours and was filtered, the washing step was repeated,

b) THF was removed from the filtered polymer by vacuum.

c) Washed with ethyl acetate according to process a), twice.

d) repeated a) twice,

e) Dry for 4 hours under vacuum.

A sample of 8 g of crosslinked polyamine and 160 ml of dry THF was stirred in a 454 g (16 oz) Fischer-Porter bottle for 4 hours. Then, 9 ml of dry methyl chloride at -78 ° C was added. they were stirred for 64 hours and the polymer was filtered after removing the methyl chloride by degassing.

Cryogenic Grinding Process

This process can be used both in the crosslinked polyamine system and in the methylated product. A sample of 9.53 g of the crosslinked polymer was ground at the temperature of liquid nitrogen for 5 minutes, to obtain 9.33 g of a fine powder. The ground material was placed in a mortar, 9.33 g of hydroxypropylmethylcellulose was added and mixed with a pestle. The product was transferred to the mill at room temperature and ground for 3 minutes. This formulation was ground in a ball mill for 9 hours and sieved through a 250 micron sieve. The reaction of 50 mg of a sample of this material with 3 ml of methanol and 3 ml of a pH 1 acid resulted in the release of misoprostol by HPLC .

Example 4

This example illustrates a drug delivery system in which misoprostol is incorporated into a crosslinked polyamine using a silyl ether linker system, where misoprostol is first covalently linked to a linker via a silyl ether and then the misoprostol-1 bonding system is attached to the previous cross-linked polymer. The process described in this example can be used to attach a drug to natural polymers, such as chitosan.

A cross-linked polyamine matrix was prepared by using a 13 g sample of a polyamine prepared by functionalization of a polybutadiene, as described in Example 1. The polyamine was subjected to cross-linking with 1.12 g of α , α'-dichloro-p-xylene in 30.3 g of THF at room temperature for 48 hours. After washing the crosslinked matrix in the manner described in Example 1, a sample of 0.948 g of the crosslinked polymer and 31 ml of THF was stirred overnight in a 100 ml round bottom flask. The linking group, after having been covalently linked to misoprostol in the manner described in Example 3 and after misoprostol having reacted with 1- (dimethylelorossi1) -2- (m, p-chloromethylphenyl letane (linker), in the amount of 45 mg, was added to the stirred mixture of the cross-linked polymer. After 48 hours, 10 ml of DMF was added. The reaction mixture was stirred for another 48 hours. The product mixture was washed with 60 ml of THF and was dried in vacuo. The reaction of a 25 mg sample of this material with 3 ml of methanol and 3 ml of pH 1 acid resulted in the release of misoprostol.

Example 5

This example refers to a drug delivery system in accordance with the teachings of the present invention, in which a drug is incorporated into a polymeric material

»S '. through an acid-sensitive connector. In particular, this example illustrates a drug delivery system in which misoprostol is incorporated into hydroxypropyl methylcellulose using an acid-sensitive silyl ether linker, ι

This example also illustrates the use of natural polymers as a basis for the delivery systems in question. The process of this example can be applied to a wide variety of natural, soluble and insoluble polymer systems. such as amino-cellulose and proteins, for example, chitosan.

21.5 mg of Misoprostol (0.0523 mmoles) were weighed in a vial and transferred to the dry box. Then, 600 mg of DMF and 3.5 mg of imidazole (0.05 mmol) were added and the mixture was stirred until they were dissolved. Finally, 10.7 mg of 1,1,4,4-tetramethyl-1,4-dichlorodisilylethylene was added and stirred for 0.5 hours. In the dry box, one gram of hydroxypropylmethylcellulose, a stirring rod and 30 ml of dry THF were added to a 100 ml flask. Next, 3.5 mg of imidazole and 1 ml of DMF were added to the solution. The reaction product from the previous step, the misoprostol disilyl chloride linker, was added and stirred for 18 hours. The solution was extracted to dryness, washed with 100 ml of toluene and filtered.

resultant was dried under vacuum.

white solid

In this way, misoprostol is covalently linked to hydroxypropylmethylcellulose by reaction with a disilyl chloride binder, the product is soluble in methanol and the HPLC analysis of a methanol solution indicates the absence of unbound misoprostol. The reaction of this product in a methanol solution of pH 1.8 indicates the release of misoprostol from the cellulose matrix.

Example 6

A series of polymeric materials of the product containing the misoprostol of Example 1 were produced, in which the amount of cross-links was varied, and swelling was studied as a function of the percentage of cross-links. The results shown in Table 1, confirm that swelling can be controlled by varying the amount of cross-links. The rate of release of a drug can be modulated by varying the extent of the cross-links. The release rate of the drug varies directly with the swelling.

TABLE 1

Number of milliequivalent cross-links of

Cross Links

- X 100 milliequivalents of nitrogen% Weight Increase at pH 1.18

10.84 525 13.85 435 17.35 289 35.28 112

Example 7

A series of crosslinked polyamines (containing about 10% crosslinked) prepared by the method of Example 1 and containing 30%, 50% and 70% of functional amine groups were evaluated for the degree of swelling at about pH of 1. It was determined that the greater the functional density of the amine, the greater the degree of swelling. The results are shown in Table 2. The rate of drug release varies directly depending on the extent of the swelling.

TABLE 2

% of Amine Quantity of Cross Links mequiv. cross-links Λ % Volume Increase <100 at a pH of 1.18 mequiv. nitrogen 30 10.8 150 50 10.0 200 70 9.4 700

Example 8

This Example refers to a system of admin istration in medications in which the enisoprost is incorporated at the system in cross-links the Example 2, using one system in

silyl ether binder.

A sample of 23.78 g of a solution of 21.03% by weight of the polyamine (5 g of polyamine) prepared by functionalizing a polybutadiene polymer in the manner described in Example 1, in toluene, was added to a Fischer flask. -Porter equipped with a stirring rod. The solution was adjusted to 50% by weight by evaporation of the solvent. Tristriphenylphosphine rhodium chloride, in an amount of 0.025 g, and 2.5 g of chlorodimethylsilane were added to the solution. After capping the • eactor, the solution was heated to 100 ° C for 17 hours. The reaction mixture was transferred to a 250 ml dry round-bottom flask in a dry box. The solution was concentrated to a 66-percent solution. weight percent by vacuum and was diluted in 20 ml of dry THF and in 20 ml of dry DMF. After 15 minutes, 0.0168 g imidazole in 0.562 THF was added slowly. After 5 minutes, 0.0945 g of enisoprost (0.247 mmoles) in 0.562 g of THF was added and washed with another amount of 0.562 of THF. for 16 hours.

bottle was capped and shaken

To the solution, 0.14 g of imidazole in 1 ml of THF was added and, after stirring, 0.236 g of methanol in 1 ml of THF were added. After stirring for 1 hour, the product solution was evaporated to remove the THF and the polymer / DMF solution was left to stand for 1 hour in order to separate from the polymer phase of the DMF. The polymeric layer was dissolved in 20 ml THF and 10 ml DMF was added. The polymeric system with the

of the

covalently bound enisoprost was isolated by removing the THF and by phase separation from the DMF. The polymer / enisoprost system was dried under vacuum. It was then crosslinked and methylated using the process described in Examples 1 and 2.

When exposed to a pH 1 acid solution released from the polyamine polymer.

the enisoprosto was

Example 9

Two grams of the silyl chloride polymer of Example 2 in a THF solution was placed in a 100 ml round bottom flask equipped with a stirring rod. DMF (8.4 ml) was added and the solution was stirred for 5 minutes. Imidazole (16 mg) was dissolved in 10 ml of THF and this mixture was slowly added to the polymeric solution and stirred for 25 minutes. A solution of 78.2 mg of the compound with the following structure was added slowly

in 5.5 ml of THF to the stirred polymer solution and the reaction mixture was stirred for 16 hours. Methanol (1 ml) was added and the solution was reduced in volume by rotary evaporation. The concentrated solution was added to a 30 ml separating funnel and was washed with 10 ml of DMF. The polymer was allowed to separate from the DMF phase. Then, the polymer was dried under vacuum and subjected to crosslinking and methylated in the manner described in Examples 1 and 2. No free compound with the previous structure was found in THF, after washing the final crosslinked methylated polymer with THF. . After exposure to an acid of pH 1, the compound with the above structure was slowly released from the polymer: after 10 minutes, 0.0966 mg of the 25.6 mg polymer compound was released; after 24 hours, 0.1968 mg of the compound was released.

Example 10

In a dry box, a 5 g sample of a polyamine prepared by functionalizing a polybutadiene polymer in the manner described in Example 1 and 4.3 g of dry toluene were added to an 85 g (3 oz) Fischer-Porter bottle . An amount of 0.025 g of chlorotristriphenylphosphine in an additional 3 g of toluene was added to the reaction mixture. While stirring, 2.5 g of chlorodimethylsilane was added and after 2 hours of stirring at room temperature, the reaction mixture was heated to 100 ° C for 17 hours. The resulting product was transferred to a 250 ml flask with THF and was concentrated to a 66.6% solution before adding 20 ml of dry THF and 20 ml of dry DMF. Then, 0.166 g (2.44 mmoles) of imidazole in 0.5 ml of THF was added and stirred for 5 minutes. After stirring, 0.627 g (2.44 mmoles) of metronidazole were added in 1 ml of THF and the solution was stirred overnight.

polymeric product was isolated by removing the THF and separating the polymer from the DMF. The polymeric product was redissolved in 10 ml of THF and in 10 ml of DMF and the polymer was isolated again by removing the THF layer. The polymer was then subjected to crosslinking in the manner described in Examples 1 and 2. Reaction of a 25 mg sample of this material with 3 ml of methanol and with 3 ml of pH 1 acid resulted in the release of metronidazole.

Example 11

Alternative Link Cruiser:

1.3,5-Tris (chloromethyl) benzene

The polyamine bound to misoprostol was prepared as in Example 1 and 3 grams of this polymer were diluted in THF to obtain 10.12 g of a THF solution. Then, 0.311 g of 1,3,5-Tris (chloromethyl) benzene in 1 ml of THF was added to this solution. Another 0.5 g of THF was added. The solution was left to stand for 54 hours to cross the polymer bonds, the crosslinked polymer was ground in an analytical mill at room temperature for 5 minutes. The resulting ground crosslinked polymer was transferred to a 2 liter glass container and was stirred in 1 liter of THF for 1 hour. The reaction mixture was allowed to settle and was filtered with a fried glass Buchner funnel. The cleaning step was carried out for a total of 5 washes with THF, obtaining 3.1 g of a cross-linked polymer, which was isolated.

Elemental Analysis:% G, 73.91; % H, 11.0:% N, 4.65; % Cl, 4.93

The crosslinked polyamine was methylated as in

Example

Dwarfs and 11.15.

Elemental

C, 65.93

H, 11.04; % N, 4.14

Cl (Vol)

Weight before swelling

Swelling Studies: pH 7 50.3 mg (5 mm] pH 1 43.5 mg (6 mm] '(Vol)

Weight after swelling

242.6 mg (10 mm) 362.0 mg (14 mm)

Volume variation in parentheses (mm).

crosslinked product swelled from pH 1 to pH 7. The crosslinked product was mixed with 50% HPMC- as described in Example 2. The reaction of a 50 mg sample of the crosslinked product with 3 ml of methanol and with 3 ml of pH 1 acid resulted in the release of misoprostol, as measured by HPLC (100% release after the first hour). The reaction of a 50 g sample of the crosslinked product with 3 ml of methanol and with 3 ml of water pH 7 resulted in the release of 1.73% of misoprostol after the first hour.

Example 12

Change in% of Cross Links:

Example 1 was followed, but instead of using 10 mole% of α, α’-dichloro-p-xylene, 17 mole% was used. In this way, 3 g of polyamine bound to misoprostol was reacted in 7.12 g of THF with 0.414 g of ,, n'-dichloro-p-xylene for 54 hours. After the cleaning process was carried out in the same manner as in Example 1, the elemental analysis of the cross-linked polymer was as follows:

% C, 73.91; % Η, 11.01;

% Ν, 4.65:% Cl, 4.65.

This material was milled as in Example 2, producing the following analysis:

% C, 65.68; % H, 10.92;

% N, 4.09; % Cl, 10.39.

Swelling Values:

Before after

Example 1 10 Mole%

Cruzad.

Soft %

Cruzad.

Example 1 10 Mole%

Mole% pH 1 49.7 mg 50, pH 7 49.6 mg 49,

Mix with 50%

6 mg 252.8 mg 242.6 mg 5 mg 541.1 mg 362.0 mg HPMC.

The reaction of this material with 3 ml of methanol and with 3 ml of calcium pH 1 resulted in the release of misoprostol.

Alternative Link Cruiser:

same process as that used in the preparation and use of the 1,3,5-tris (chloromethyl) benzene

Example 11. In a 100 ml round-bottom flask, 2.21 g of polyamine bound to misoprostol (7.45 g of a 29.63% solution in THF) was added. To the flask, 0.25 g (0.00103 moles) of 1,6-dibromoexane in 1 ml of THF was added with stirring. The crosslinking reaction was allowed to proceed for 54 hours. The cleaning procedure described in Example 1 was followed.

Elemental analysis:% C, 73.12; % H, 11.63; % N, 4.97; % Br, 5.92.

The crosslinked polyamine was methylated according to the procedure of Example 2.

Elemental analysis:% C ·, 64.93; % H, 11.38; % N, 4.06; % Br, 2.53; % Cl, 9.74.

Swelling Values:

Before mg (mm)

After mg (mm) ρΗ 1 pH 7

48.8 mg (6 mm) 49.5 mg (6 mm)

296.8 mg (14 mm) 910.1 mg (22 mm)

Example 14

FeniImeti1chlorosi1ilo connector

An aliquot of 34.88 g of a polyamine solution (10 g of polyamine in toluene) was added to a Fischer-Porter bottle equipped with a stirring rod. The solution was concentrated and adjusted to 50% by weight in toluene. After transfer to a dry box, 0.1 g of chloride was added

of chlorotristriphenylphosphinorodium to the polyamine solution and stirred for 5 minutes. Next, 0.952 g of phenylmethylchlorosilane was added. After capping and removing the reactor from the dry box, the solution was heated to 100 ° C for 17 hours. In the dry box, the reaction solution was transferred to a 250 ml round bottom flask and diluted to 50 g with THF. After adding 25 g of DMF and stirring for half an hour, THF and toluene were removed by vacuum

The polymeric mixture was transferred to a separating funnel.

phase, the phase

After separation of the polymer the lower DMF was removed, dissolved in 50 g of THF and stirred with 40 g of DMF for half an hour. THF was removed by vacuum and the polymer phase was separated. The resulting phenylmethyl chlorosylated polymer (9.83 g) was diluted with 34.95 g of THF and with 37.06 g of DMF. Then, 0.109 g of triethylamine (0.514 mmoles), 0.35 g of imidazole (0.514 mmoles) and 0.197 g of misoprostol (0.514 mmoles) were added. This solution was stirred for 17 hours. After 17 hours, 0.298 g of triethylamine, 0.2 g of imidazole and 0.417 g of methanol were added and stirred for 1 hour. The product solution was then evaporated to remove all of the DMF and was left to stand for 1 hour to phase out the polymer from the DMF solution. The crosslinking and methylation process was carried out according to Examples 1 and

Elemental analysis after% cross link% N 5.41

After methylation

75.48; /O H 10.52 5.41: O/ Z-3 Cl 3.49 68.60; O/ zo H 10.89 4.46; O/ zo Cl 11.45

».

X *

The reaction of a 50 mg sample of the methylated material with 3 ml of methanol and 3 ml of pH 1 acid resulted in the release of misoprostol, as observed by HPLC (80% release after one hour). The reaction of a 50 mg sample with 3 ml of methanol and 3 ml of pH 4 acid resulted in the release of 1% misoprostol after 2 hours.

Examples 15 to 18

For Examples 15 to 18, the procedure of Example 14 was followed, except that the phenylmethylchlorosilyl ligand * used was replaced by the following silane binding agents,

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Example 19. Processes for the Individual Isomer with the Cruiser '

Isopropyl Ethyl Bonds a ·) Polybutadiene hydroformylation

Under a stream of nitrogen, an autoclave of

2.0 liters with 289.0 grams of polybutadiene, with 308 ml of toluene, with 12.7 g of triphenylphosphine and with 0.27 g of hydrocarbonyl tristriphenylphosphinorodium. The reaction was heated to

80 ° C under nitrogen and was then charged with 21.09 kg / cm (300 psi) of C0 / II „and stirred at 1000 rpm, until 33.5% z of the butadiene units hydroformylated. The reaction was practically complete at the end of the reaction. THE

3.5 hours, mixing

Protonic NMR confirmed the extent of the reaction was removed from the autoclave and toluene was used to assist the transfer. The solution was filtered to remove particulate elements and was concentrated to 500 g. A 250 gram portion of this solution was slowly dipped in 1000 ml of methanol / water (80/20, v / v) with stirring. After stirring for an additional 15 minutes, stirring was stopped and the reaction mixture was left to settle for 1 hour. The lower polymeric layer was isolated and the washing step was repeated, the dried polymer was redissolved in toluene and stored in the dark.

b) Reducing amination of the polyaldehyde in polyamine toluene was removed from the polyaldehyde by means of a vacuum. Then, the polyaldehyde (300.29 g) was diluted with 785 ml and divided into two separate portions. A 2 liter autoclave was loaded with 150 DMF. The reducing amination mixture.

grams of polyaldehyde in 392.5 ml of DMF. 330 ml of cyclohexane.

112 g of dimethylamine and 1.5 g of ruthenium carbonyl, the autoclave was closed and purged quickly with 7.03 kg / cni (100 psi) of CO / Hg and 63.27 kg / cm * (900 psi) of Hg. The autoclave was heated to 120 ° C at 1000 rpm. The gas evolution started at about 30Â ° C. The reaction ended when the gas evolution ended. After cooling to room temperature, the contents were removed from the autoclave and placed in a 1 liter separation funnel and the phase separation was allowed to be discarded at the lower DMF level. a separating funnel 300 ml of DMF and cyclohexane to redo the original volume. The separation process was repeated. The DMF extraction process was performed a total of three times. The cyclohexane layer was filtered with a medium porosity Buchnei * funnel and rotoevaporated at 50 ° C with toluene to remove residual DMF.

that. It was removed and reddish brown.

c.) Hydrosilylation of polyamine g polyamine (34.88 g of a polyamine / toluene solution) were placed in a 170 g Fischer-Porter bottle (8 os). After capping, most of the toluene and air were removed by vacuum distillation with stirring. The reactor was placed in a dry box, 0.1 g of chlorotristriphenylphosphinorodium and 9.58 g of toluene were added to bring the solution to 50% by weight. Then, 0.741 g of isopropylethylchlorosilane was added. The reactor was capped and heated to 100 ° C, using a temperature-controlled oil bath, for 17 hours. The reaction was transferred to a dry box and the solution was transferred to a dry 250 ml round bottom flask equipped with a stirring rod. The reactor was washed with dry THF and a total of 50 g of THF was added to the reaction product. Then, 50 ml of dry DMF was added and

stirred for 0.5 hours. The THF and toluene were removed by vacuum and the polymer was separated from the remaining DMF solution. The reaction mixture was poured into a 125 ml separating funnel and was left in phase separation for 1 hour. The lower DMF layer was removed. The polymer was redissolved with 50 g of dry THF. 40 g of DMF were added and the washing process was repeated in silmutaneous with the separation process. The polymer was redissolved in 100 ml of dry cyclohexane and extracted with 80 ml of DMF. 20 ml of cyclohexane was added to the cyclohexane phase and extracted again with 80 ml of DMF. The clean polymer was stored in dry THF.

D.) Binding of the individual isomer of misoprostol to the silyl chloride polymer silyl chloride polymer 80% by weight (total of 16,014 g of polymer) was concentrated to and 57 g of THF and 60.5 g of DMF were added. 0.022 g of triethylamine in 0.3 g of THF and 0.008 g of imidazole in 0.3 g of THF were also added under stirring. Then, 0.0441 g of the individual bioactive isomer (11R, 16S) of misoprostol was added, with the following structure:

CH, and stirred for 20.5 hours at room temperature. The binding was controlled by TLC. The reaction was quenched by adding 0.87 g of triethylamine, 0.583 g of imidazole and 1.4 g of methanol and was stirred for 1 hour. After removing the dry box, the THF was removed by distillation and the remaining solution was transferred to a separatory funnel and was left in a phase separation process for 1 hour. The polymer was redissolved in 85 ml of THF and 60 ml of DMF and was stirred for half an hour. The THF was removed and the DMF was separated from the polymer by means of a separating funnel. 14.21 g of polymer was collected.

Crosslinking of the individual misoprostol-prepolymer prepolymer isomer from step d.) (14.2 g) was dissolved in 33.2 g of THF and then 1.13 g of ether, α '-dichloro- p-xylene. It was left in agitation until the connections were crossed. The reaction was allowed to settle for 60 hours. The crosslinked polymer was cut with a spatula and ground in an analytical mill. The polymer was stirred with 1400 ml of THF and filtered with a coarse filter. Washing was repeated five times.

600 ml. The process of

Elemental Analysis% C, 74.01:% H.

11.15; % N

5.28; % Cl, 3.86.

Methylation of the dry THF cross-linked polyamine cake from the previous step e) was placed in a 340 g (12 oz) Fischer-Porter bottle equipped with a stirring rod. CLF grade THF was added to give a total volume of 245 ml (pre-measured in the bottle). The bottle was capped and the solution was stirred and cooled to dry ice temperature for half an hour. Methyl chloride was added until a 20% volume increase was obtained (to a pre-measured volume of 294 ml). The solution was stirred for 60 hours. The reactor was vented and purged with nitrogen. Using a coarse filter, the mixture was filtered and then washed with 1400 ml of THF. After filtration, the residue was dried on a vacuum line for 6 hours. A small sample was removed and dried overnight at 50 ° C - for elemental analysis:% C, 67.245; % H, 10.96:% N, 4.52; % Cl. 11.41; Cl / N = 0.997.

polymer was placed in an analytical mill equipped with a cryogenic cap. The mill was placed in a glove bag and, while being subjected to nitrogen, it was ground at the temperature of liquid nitrogen. The ground polymer was allowed to warm up under nitrogen to prevent moisture formation. The ground polymer was sieved through a 250 micron sieve and the 250 micron material (13.84 g) was mixed with 13.84 g of HPMC. The mixture was mixed in an analytical mill for 1 minute. The mixture was transferred to a ball mill and ground for 12 hours. The resulting mixture was sieved through a 250 micron filter. The collected polymer (26.86 g) was placed in an amber bottle and was stored in a freezer.

Example 20

Synthesis of the Diisopropyl Drug Administration System with the Individual Misoprostol Isomer

a.) Polyamine hydroxylation

12.0 g of polyamine (33.5% amine; 28.67% by weight in toluene) were weighed in a tared Fischer-Porter bottle of 170 g (6 os), equipped with a magnetic stirring rod. The Fischer-Porter bottle was closed and the toluene was removed in vacuo. The bottle was taken into a dry box still under vacuum. The polymer was redissolved to 50% in toluene with 12.0 g of toluene and 0.120 g of chlor-tris (triphenylphosphine) rhodium (I) (Chemical Stream) was added to the polymer solution. Diisopropylchlorosilane (0.981 g, 6.52 mmol; Huls America) was weighed in a flask and added slowly to the polymer solution. The Fischer-Porter bottle was closed and removed from the dry box. Then it was placed in a temperature-controlled oil bath at 100 ° C and stirred for 24 hours.

b.) Washing with DMF after hydrosilylation

After 24 hours, the Fischer-Porter bottle was removed from the oil bath and transferred to the dry box. The polymeric solution was transferred to a 250 ml round bottom flask equipped with a magnetic stirring rod. Tetrahydrofuran (THF) was added to the solution to obtain 50 g of solvent. 25 g of DMF was added to the polymer solution and the mixture was stirred for 30 minutes. The THF and toluene were removed in vacuo and the polymer-DMF mixture was transferred to a 125 ml separating funnel and left in phase separation for 17 hours. The bottom layer (DMF) was drained into a small bottle. The top layer (polymer) was washed in a 250 ml round bottom flask with 50 g of THF. 40 g of DMF was added to the THF-polymer solution and the solution was allowed to stir for 30 minutes. The THF was removed in vacuo and the DMF-polymer mixture was transferred to a 125 ml separating funnel and left in phase separation for 17 hours. The bottom layer (DMF) was drained into a small bottle and the polymer was washed into a 250 ml round bottom flask with THF.

c,) Bonding of the Individual Misoprostol Isomer to the Silyl Cide Polymer

The polymer-THF solution was concentrated in vacuo to 80 weight percent. The solution was diluted with THF (4 ml / g polymer) and DMF (4 ml / g polymer) and was transferred to a 250 ml 3-neck flask. To this solution, triethylamine (0.03 g, 0.30 mmol), DMAP (0.0375 g, 0.30 mmol) and the individual isomer misoprostol (0.060 g, 0.15 mmol) were added. The vial was capped with rubber septa and removed from the dry box. The flask was placed in a temperature controlled oil bath at 50 ° C for 20 hours. The binding of the drug to the polymer was controlled by Thin Layer Chromatography (CCF). After 20 hours, the reaction was quenched by adding triethylamine (0.42 g), DMPA (0.50 g) and methanol (0.66 g), which converts all the remaining silyl chloride groups of the polymer into groups of silylmethoxy. This solution was stirred for 1 hour and the THF was removed in vacuo. The mixture of

DMF-polymer transferred to a 125 ml separating funnel and left in phase separation for 1 hour. The bottom DMF layer was drained into a small bottle and the polymer was transferred into a 250 ml bottle with 35 ml THF. DMF (35 ml) was added to the polymer solution and the solution was stirred for 1 hour. The THF was removed in vacuo and the polymer-DMF mixture was transferred to a 125 ml separating funnel and left in phase separation for 1 hour. The lower DMF layer was poured into a small bottle and the polymer was redissolved in THF. The polymeric solution was filtered through a thick funnel of fried glass. The filtered polymeric solution was pumped to dryness in a vacuum line. The subsequent steps of crosslinking, methylation and grinding were carried out in the manner detailed in the previous Examples.

Example 21

Preparation of the Silyl Ether Product of metronidazole and phenylmethylelossi1i1-2- (p-chloromethylphenyl) ethane:

A solution of 12.98 g of phenylmethylchlorosilyl-2 ~ (p-chloromethylphenidane in 100 ml of anhydrous dimethylformamide was immersed in a solution of 8.98 g of metronidazole and 7.14 g of imidazole in 400 ml of anhydrous dimethylformamide at room temperature with stirring. magnetic and under positive nitrogen pressure for 20 hours.

The reaction product was isolated by placing the reaction mixture inside a separating funnel containing 250 ml of diethyl ether and 750 ml of water. The ether and the aqueous phases were separated and the aqueous phase was washed 3 times with 250 ml portions of ether. The combined ether extracts were washed 5 times with 150 ml portions of water and once with a 300 ml portion of a saturated aqueous NaCl solution. The ethereal solution was dried over MgSO ₁ and extracted on a rotary evaporator, followed by further drying on a high-vacuum line, crude product was collected in methylene chloride and treated in a preparative HPLC column, using mixtures of 10/90 and 50/50 volume percentages of ethyl acetate and hexanes, respectively, as eluents.

Preparation of the Polyamine Adduct with Previous Silyl Ether:

27.23 g (36.8 mmoies) of dry polymer were dissolved in 35 ml of anhydrous tetrahydrofuran under nitrogen. The metronidazole silyl ether product was dissolved in 12.4 ml of anhydrous tetrahydrofuran and immersed in a polymeric solution at room temperature with stirring. After stirring for 24 hours, 83.4 ml of anhydrous tetrahydrofuran was added and, after half an hour, dipped in a solution of 2.16 g of α, to: '- dichloro-p-xylene in 10 ml of anhydrous tetrahydrofuran, The resulting mixture was stirred for 18 hours. The reaction mixture was subjected to crosslinking overnight and left at room temperature for 5 days, product was milled in an explosion-proof Waring mixer containing 550 ml of anhydrous tetrahydrofuran and by filtration at the same time. it was protected from atmospheric humidity. This operation was repeated once. The finely divided product was dried on a rotary evaporator, followed by drying overnight in a vacuum line.

Analysis of Metronidazole In Vitro Release at pH 2:

A heavy amount (+ 50 mg) of the medicine metoonidazole / 1 / binder / polymer was mixed and 6.0 ml of diluted aqueous HCl, pH 2, in a culture tube with a teflon-coated cap and which was equipped with a magnetic stirring rod The mixture was stirred for certain periods of time and centrifuged and then a 250 g aliquot was removed and analyzed by HPLC to determine the metronidazole content in mg / ml.

Using this method, 3% by weight of metronidazole was released over 30 minutes and 9.5% by weight was released over 24 hours (% by weight of a 50 g sample).

This example demonstrates a 9.5 wt% incorporation of a drug in a crosslinked polyamine.

Example 22 The procedure of Example 15 was repeated in all essential details, except that the active ingredient was the individual bioactive isomer (11R, 16S) of misoprostol, as used in Examples 19 and 20. The pharmacological values for the resulting system are shown in Table 8.

The procedure of Example 20 was repeated in all essential details, except that the linking group was chlorine (t-buti1) methylIsilane and the active ingredient was misoprostol. The misoprostol was released from the polymeric delivery system under pH '1 conditions.

Example 24 The procedure of Example 20 was repeated in all essential details, except that the linking group was chloroisobutylisopropylsilane. The active ingredient was the only bioactive isomer of misoprostol. The misoprostol isomer was released from the polymeric delivery system under pH 1 conditions.

Experi ence 1

Plasma Concentration

The concentration of misoprostol free acid in plasma was measured for the purpose of administering misoprostol using a drug delivery system prepared in the same manner as in Example 2. The system in question delivers misoprostol at a rate sufficient to provide an action local gastric therapy, without any significant systemic side effects, when compared to misoprostol administered via the hydroxypropylmethylcellulose (HPMC) vehicle, in which misoprostol is administered to it. The results, reported in Table 3 and illustrated in Figure 1, show that the polymer delivery system of Example 2 reduces the peak plasma level and total systemic exposure to free acid in misoprostol relative to the HPMC formulation. the polymeric delivery system produced prolonged levels in the plasma of misoprostol-free acid for the duration of the study (6 hours for 400 pg / kg dosage), which indicates a prolonged gastric residence time and an availability of misoprostol at from the polymeric administration system.

TABLE 3

TIME FOR 0 PEAK (HOURS) CONCENTRATION PICO (pg / ML) 3 AUC ¹ SYSTEMIC EXPOSURE ² IN% HPMC as a vehicle the 0.5 4100 4770 - (400 pg / kg) POLYMER 2.0 1 01 x O x 402 8.4 (100 pg / kg) POLYMER 2.0 646 2790 58.5 (400 pg / kg) ¹ Area under pl concentration curve asthma- time since the time 0 to 6 hours, 2 Relative to dose of 400 pg / kg of HPMC that is considered 100%, 3 _π - Picograms by mililitr O . Experience 2 Challenge Regarding Gastric Mucosa Damage Induced by

Indomethacin

Male Charles River rats [Cri: COBS, CD (SD) BR], 180-210 g body weight, were deprived of food, with water available ad libitum for twenty-four hours before the study, On the day of the experiment, the rats were randomly divided into groups of six rats each. The misoprostol / HPMC (3, 10, 30 and 100 pg of misoprostol / kg), HPMC (10.1 mg / kg), the polymer / misoprostol system of Example 2 (1, 3, 10 and 30 pg of misoprostol / kg referred to in Table 4 as the System of Example 2) or the polybutadiene polymer (containing no amount of misoprostol) from Example 2 (polymer / HPMC, 9.1 mg / kg referred to in Table 4 as the Polymer of Example 2). dissolved or suspended in distilled water, it was administered intragastrically (10 ml / kg) to groups of six rats. Thirty minutes after dosing, each rat received 16 mg / kg of indomethacin (Sigma Chemical Co.) intraperitoneally in a 0.5% aqueous methyl cellulose solution (4000 cps., Sigma Chemical Co.) (10 ml / kg). Five hours later, the animals were sacrificed for CO 2 asphyxiation. Each stomach was removed, cut open along the great curvature and washed gently with tap water. The glandular portion of the gastric mucosa was examined using a stereomicroscope. with a 10x magnification. Gastric lesions were counted without knowledge of treatment. The values of the two experiments were gathered and significance (P <0.05) was determined using one-way analysis of variance and Dunnett's multiple comparison process. The results of the experiment are shown in Table 4 below. The polymer / misoprostol delivery system, such as that of misoprostol / HPMC, showed activity against indomethacin-induced gastric gland damage in the rat. k minimum effective dose was the same for each preparation, ie 10 .ug / kg intragastrically.

TABLE 4

Effect against Indomethacin-induced gastric damage in the rat

Treatment i Dose (pg Miso / kg i.g.) N2 of Injuries Gastric / Rat (x ± S. AND. ) HPMC - 18.2 + 2.9 Miso / HPMC 3 15.0 ± 2.6 10 6.3 + 1.8 30 4.6 + 1.8 100 2.3 ± 0.9 Ex. 2 polymer - 17.3 + 2.8 Ex 2 system 1.0 17.1 + 3.1 3.0 14.2 ± 2.3 10.0 8.6 ± 2.4 30.0 0.7 ± 0.3

Experience 3

Challenge Against Alcohol-Induced Gastric Mucosa Damage

Male Charles River rats weighing 180-210 g, deprived of food for 24 hours, were dosed intragastrically (10 ml / kg) with misoprostol / HPMC (100, 200, 400 or 600

pg of misoprostol / kg), or with HPMC (60.6 mg / kg) dissolved in distilled water, or with the polymer / misoprostol system of Example 2 (50, 100, 200 or 400 pg of misoprostol / kg) referred to in Table 5 as Ex. 2 system) suspended in distilled water, or with the blank polybutadiene polymer (which did not contain misoprostol) from Example 2 (polymer / HPMC, 125 mg / kg, referred to in Table 5 as Ex. 2 Polymer) suspended in distilled water. Four hours later, each rat received absolute ethanol. An hour after the rats were killed by asphyxiation

ç.

rat was removed, opened and gently tap washed. The glandular portion of the gastric mucosa was examined at the spheromicrocope with a 10x magnification. Gastric lesions were counted by an investigator on the treatment performed. 1 ml of methanol administration was determined intragastrically. as with C0 ₍ each stomach with water from the 'relatively significant blind' (i

0.05) by using one-way analysis of variance and by Dunnett's multiple comparison process. The are reported in Table 5, results

TABLE 5

Effect Against Alcohol-Induced Gastric Damage in the Rat

Treatment ( Dose ug miso / kg i.g.) N2 of Injuries % Variations Gastric / í latazana HPMC - 20.5 ± 2.0 Miso / HPMC 100 20.1 ± 2.9 -1.9 200 15.9 ± 2.0 -22.4 400 10.8 ± 3.3 -47.3 600 7.3 ± 2.0 -64.4 E polymer x. 2 24.2 ± 2.3 Ex system . 2 50 21.6 ± 2.1 -10.7 100 16.4 ± 2.1 -32.2 200 8.8 ± 2.6 -63.6 400 3.0 ± 1.1 -87.6 I expei iency 4 Procedure for Evaluation of Diarrhea due to Intra-administration

intestinal: COBS, CD (SD) BR], food, but at four hours, rats were

Charles River male rats [Cri

180-210 g of body weight were deprived of water ad libitum for twenty before the study. On the day of the experiment, those randomly divided into groups of six rats each. Each rat was anesthetized with methoxyflurane, the abdomen was opened and the first part of the small intestine was exteriorized. The misoprostol / HPMC (215-1000 µg misoprostol / kg), HPMC (68.8 mg / kg), the polymer / misoprostol system of Example 2 (316-1470 µg misoprostol / kg referred to in Table 6 as the Ex System . 2), or the blank polybutadiene polymer (which does not contain misoprostol) from Example 2 (polymer / HPMC, 445 mg / kg referred to in Table 6 as E polymer <: 2), dissolved or suspended in distilled water, it was injected into the intestinal lumen using a 23 gauge hypodermic needle. The abdominal incision was closed with wound clips and collodion. The rats were placed in individual netting cages and the collection trays were lined with Kraft paper. Diarrhea was assessed on an all-or-nothing basis, at hourly intervals, for eight hours after treatment. Diarrhea was defined as shapeless or watery stools that wet the lining paper. The DE ^ q value corresponding to the eighth hour for misoprostol / HPMC was calculated using a logistic regression model. The system in. dimer / misoprostol from Example 2 did not show diarrhea at the doses tested, which indicated that no significant amount of misoprostol was released in the intestine.

- 65 TABLE 6

Diarrhea Activity Following Intraintestinal Administration in the Rat

Dose Rat No. 2. with Diarrhea (8 hrs) Treatment (ug Miso / kg) R2 N2 Treated sanas HPMC - 0/6 Miso / HPMC 215 0/6 316 1/6 DEj-q = 534 jjg / kg 464 3/6 (95% C.I., 377, 757) 681 4/6 1000 5/6 Ex polymer, , 2 --- 0/6 Ex system. 2 316 0/6 681 0/6 1470 0/6

Experience 5

Procedure for Assessment of Diarrhea by Intragastric Administration

Male Charles River rats [Cri: COBS, CD (SD) BR], 190-210 g body weight, were deprived of food, but with water available ad libitum for twenty-four hours, prior to the study. On the day of the experiment, the rats were rats randomly divided into groups of three rats each. 0 misoprostol / HPMC (68, 100, 147, 215, 316, 464 and 681 pg misoprostol / kg). HPMC (68.8 mg / kg), the polymer / misoprostol system of Example 2 (100, 215, 316, 464, 681, 1000 and 1470 Gg of misoprostol / kg referred to in Table 7 as the Ex. 2 system) or blank polybutadiene polymer without misoprostol) of Example 2 (polymer / HPMC, 445 mg / kg referred to in Table 7 as Polymer of Ex. 2), dissolved or suspended in distilled water, was administered intragastrically (10 m / kg) to the groups of three rats each. The rats were placed in individual wire mesh cages and the collection trays were lined with Kraft paper. Diarrhea was assessed on an all-or-nothing basis. at hourly intervals for eight hours after treatment. Diarrhea was defined as stool without ovens or watery stools that wet the lining paper. The values of the two experiments were combined and the DEj-θ values were calculated using a logistic model. A likelihood relationship test was used to determine whether the DE _rn values were significantly different, or

The results of the study are summarized in Table 7. The polymeric system with misoprostol was significantly less diarrhea in the rat than misoprostol / HPMC, with agas ^ θ values intragastrically 715 and 265 pg misoprostol / kg, respectively,

TABLE 7

Diarrhea activity following intragastric administration in the rat

Dose Rat No. 2. with Diarrhea (8 hrs) Treatment (pg Miso / kg) N2 of Treated Rats HPMC - 0/6 Miso / HPMC 68 0/6 100 1/6 147 2/6 215 0/6 316 5/6 DEg ₀ = 265 pg / kg 464 4/6 (95% C.I., 188. 388) 681 6/6 Ex polymer, O _ > e » 0/6 Ex system. 2 100 1/6 215 1/6 316 2/6 464 1/6 DE5o = 715 pg / kg 681 2/6 (95% C.I., 378, 1352) 1000 3/6 1470 6/6

The studies reported in Table 5 show that misoprostol / HPMC was active against gastric damage induced by ethanol at 400 pg misoprostol / kg when administered intragastrically four hours before ethanol, so that the polymer / misoprostol delivery system produced a effect equivalent to 100 Hg of misoprostol / kg, suggesting a uniform availability of misoprostol from the polymeric delivery system of Example 2. The delivery system of Example 2 and misoprostol / HPMC showed the same activity against gastric damage induced by indomethacin with an minimum effective dose of 10 µg misoprostol / kg for each preparation. In contrast to the efficacy studies, the delivery system in Example 2 was significantly less diarrhea than misoprostol / HPMC, with ΏΕ ^, θ values of eight hours, respectively, 715 and 265 pg misoprostol / kg, as is shown in Example 15, In addition, no diarrhea was observed by intestinal administration of the polymer / misoprostol system of Example 2, indicating that no significant amount of misoprostol was released in the rat intestines, whose pH is about 7 or higher.

Although the system has been described here with certain details in mind, further modifications to the polymeric system can be made to achieve changes in the rate of release of an active ingredient from said delivery system. For example, the percentage and nature of auxiliary groups in the main polymer structure can be modified, the extent of crosslinking can be modified, and the steric and electronic environment of the hydrolyzable covalent bond with the drug can also be modified (for example, the linker group can be modified from a dimethylsilane group to a diphenylsilane, or these two linkers can be employed in the same polymeric delivery system to provide a uniform / controlled release rate).

ϊ

AD TABLE 8 below shows the results of experiments with certain polymeric delivery systems described here, in which the steric and electronic environment of the hydrolyzable covalent bond with the drug has been changed. The table shows the results for certain polymeric delivery systems for anti-ulcer activity against gastric damage by Indomethacin. as well as the results of studies to define the diarrhea activity of administration systems. compared to a misoprostol / HPMC dispersion. The results show that the delivery systems retain anti-ulcer activity and have lesser diarrheal side effects (i.e., diarrhea, if any, has been recorded at a higher concentration for delivery systems than for the misoprostol / HPMC dispersion).

TABLE 8

Pharmacological Summary of Polymeric Administration Systems Replaced by Silicon Compared to Miso / HPMC

Replacement System Medication Activity Anti-ulcer Di Gastric Damage by Indomethacin Activity Irregular P > or Silicon Ex. 1 Me ₂ Miso 9.7 715 Miso / HPMC- 13.2 265 Ex, 18 Et _p Miso 7.7 910 Miso / HPMC 9.5 290 Ex. 14 PheMe Miso 7.0 858 Miso / HPMC 7.6 325 Ex. 15 Pk ₂ Miso 16.0 2031 Miso / HPMC 27.1 485 Ex. 17 (Isopropyl) _o Miso 32.6 No diarrhea the 1856 Ex. 22 Ph ₂ (11R, 16S) $ 4.3 515 Isomer Miso / HPMC 24.9 316 Ex. 19 Isopropyl / Et (11R.16S) Isomer 4.1 329 Miso / HPMC 27.7 321

• »>

s-.

Ε?;. 20 (Isopropi 1) „(11R.16S '

Miso / HPMC lsomero

17.8

Individual bioactive isomer of misoprostol

No diarrhea

Claims (31)

I ^a . - Process for the preparation and administration system for the release of an active ingredient at pH values of about 7 and for inhibiting the release of the active ingredient at pH values above 7, characterized by fixing the active ingredient to a functionalized polymer through a pH sensitive covalent bond and capable of being broken in the pH ranges up to about 7, which active ingredient is administered in typical compositions that contain it in an effective amount of about 1M to about 1g, the linking group being able be attached to the functionalized polymer prior to covalent attachment to the active ingredient or the linker group is covalently attached first to the active ingredient and the linker / active ingredient is then attached to the functionalized polymer. 2 ^a . Process according to Claim 1, characterized in that the covalent bond between the active ingredient and the polymeric material comprises a covalent bond of acetal, thioacetal, imine, aminal, carbonate, vinyl ether, silyl ester or silyl ether. 3 ^a . Process according to Claim 2, characterized in that the polymeric material is linked to the active ingredient through a covalent bond of silyl ether. 4 ^a . Process according to Claim 3, characterized in that the polymeric material comprises a polymer with a silyl portion. 5-. Process according to Claim 4, characterized in that the polymer comprises the silyl portion in the main structure or along a branch of the main structure of the polymeric material. 6 ^a . Process according to Claim 1, characterized in that the polymer is practically non-absorbable and physiologically active. 7 ^a . Process according to Claim 6, characterized in that the polymer comprises a polymer selected from polyamides, polybutadienes, copolymers of 1,3-dienes, polysaccharides, hydroxypropylmethylcellulose and polymers of acrylic and methacrylic acid, including their copolymers, maleic copolymers and one polymer with derivable olefinic bonds. 8 ^a . Process according to Claim 7, characterized in that the polymer is selected from a polyamine, a polybutadiene, copolymers of 1,3-dienes and a polymer with a derivable olefinic bond. 9 ^a . Process according to Claim 8, characterized in that the polymer comprises a polyamine. 10 ^a . Process according to Claim 8, characterized in that the polymer comprises a polybutadiene. 11 ^a . Process according to Claim 6, characterized in that the polymer is cross-linked to provide the non-absorbable property. 12 ^a . Process according to Claim 11, characterized in that the cross-linking agent may be a dialdehyde, a diacid, a disilane, a dialoxylene, a tri (halomethyl) benzene, a dialoalkane, a dialoalkene, a diallylide or any polyaromatic halide, aliphatic or allylic, and the like. 13 ^a . Process according to Claim 1, characterized in that the active ingredient is covalently linked to the polymer through a linking group. 14 ⁴ . Process according to Claim 13, characterized in that the linking group comprises a group that forms a bond with the active ingredient which is a covalent bond of acetal, thioacetal, imine, aminal, carbonate, vinyl ether, silyl ester or ether of silyl. 15 *. Process according to Claim 14, characterized in that the linking group comprises a silyl linking group with the structure P-Si-Y-D where P is a polymer, Y-D is the active ingredient, y 1! representing -0- or the group -0-C-; R ₁ and R ₂ are independently H or substituted or unsubstituted alkyl, cycloalkyl, alkenyl, alkynyl, aryl, alkaryl or aralkyl groups. 16. A process according to Claim 15, characterized in that the linking group comprises a group that forms a covalent bond of the silyl ether type. 17. The process of Claim 16 wherein the linking group is selected from chlorodiisopropylsilane, chloroisopropylethylsilane, chlorodimethylsilane, chlorodiphenylsilane, l- (dimethylchlorosylyl) -2- (m, p-chloromethylphenyl) ethane el, l, 4,4-tetramethyl-1,4-dichlorodisylethylene, chlorophenylmethylsilane, chlorine (t-butyl) methylsilane, chloroisopropylisobutylsilane and chlorodiethylsilane. 18. The process of Claim 17 wherein the linking group is chlorodiisopropylsilane. 19. The process of Claim 17 wherein the linking group is chloroisopropylethylsilane. 20®.- A process according to Claim 1, characterized in that the active ingredient comprises a compound containing a hydroxyl group, a carboxylic acid group, an amino group or an -NHR group where R is an alkyl group of 1 -4 carbon atoms, a thiol group or an enolizable carbonyl group. 21. The process of Claim 20 wherein the active ingredient contains a hydroxyl functional group. 22. The process of Claim 21 wherein the active ingredient is selected from a natural or synthetic prostaglandin or prostacyclin. 23. The process of Claim 22 wherein the active ingredient comprises a prostaglandin analog with the structure OR where R represents hydrogen or lower alkyl having 1 to 6 carbon atoms; R _x represents hydrogen, vinyl or lower alkyl having 1 to 4 carbon atoms and where the wavy line stereochemically represents R and S; R ₂ , R ₃ and R 4 are hydrogen or lower alkyl having 1 to 4 carbon atoms or R ₂ and R ₃ together with carbon Y form a cycloalkenyl having 4 to 6 carbon atoms or R ₃ and R ₄ together with the X and Y carbons form a cycloalkenyl with ΊΊ 4 to 6 carbons and where the XY bond _; it can be saturated or unsaturated. 24 ^a .- Process according to a. Claim 23, characterized in that the active ingredient comprises a misoprostol. 25. ^A process according to Claim 23, characterized in that the active ingredient is a compound with the following structural formula: 26. ^A process according to Claim 25, characterized in that the linking group is chlorodiisopropylsilane. 27. ^A process according to Claim 25, characterized in that the linking group is chloroisopropylethylsilane. 28. ^A process according to Claim 25, characterized in that the linking group is chlorodiphenylsilane. 29. ^The process of Claim 23, wherein the active ingredient comprises enisoprost. 30 ⁴ .- _s method according to claim 21, wherein the active ingredient comprises metronidazole. 31. The method of Claim 1, wherein the polymer is adapted to swell at pH values between about 1 and 7.